In order to improve the specific delivery of drugs with a low therapeutic index, several drug carriers such as liposomes, microparticles, nano-associates (e.g. polymeric micelles, polyion complex micelles (PICM)) and drug-polymer conjugates have been studied. In recent years, water-soluble supramolecular assemblies such as polymeric micelles and PICM have emerged as promising new colloidal carriers for the delivery of hydrophobic drugs and polyions (e.g. antisense oligonucleotides), respectively.
Polymeric micelles have been the object of growing scientific attention, and have emerged as potential carriers for drugs having poor water solubility because they can solubilize those drugs in their inner core and they offer attractive characteristics such as a generally small size (<300 nm) and a propensity to evade scavenging by the mononuclear phagocyte system.
Micelles are often compared to naturally occurring carriers such as viruses or lipoproteins. All three of these carriers demonstrate a similar core-shell structure that allows for their contents to be protected during transportation to the target cell, whether it is DNA for viruses or water-insoluble drugs for lipoproteins and micelles.
Polymeric micelles seem to be one of the most advantageous carriers for the delivery of poorly water-soluble drugs as reported by Jones and Leroux, Eur. J. Pharm. Biopharm. (1999) 48, 101-111; Kwon and Okano, Adv. Drug Deliv. Rev. (1996) 21, 107-116 and Allen et al. Colloids Surf. B: Biointerf. (1999) 16, 3-27. They are characterized by a core-shell structure. The hydrophobic inner core generally serves as a microenvironment for the solubilization of poorly water-soluble drugs, whereas the hydrophilic outer shell is responsible for micelle stability, protection against opsonization, and uptake by the mononuclear phagocyte system.
Pharmaceutical research on polymeric micelles has been mainly focused on copolymers having an AB diblock structure with A, the hydrophilic shell moieties and B the hydrophobic core polymers, respectively. Multiblock copolymers such as poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) (A-B-A) can also self-organize into micelles, and have been described as potential drug carriers, e.g. Kabanov et al., FEBS Lett. (1989) 258, 343-345. The hydrophobic core which generally consists of a biodegradable polymer such as a poly(β-benzyl-aspartate) (PBLA), poly(D,L-lactic acid) or poly(□-caprolactone), serves as a reservoir for a poorly water-soluble drug, protecting it from contact with the aqueous environment. The core may also consist of a water-soluble polymer, such as poly(aspartic acid) (P(Asp)), which is rendered hydrophobic by the chemical conjugation of a hydrophobic drug, or is formed through the association of two oppositely charged polyions (PICM). Several studies also describe the use of poorly or non-biodegradable polymers, such as polystyrene (PSt) or poly(methyl methacrylate)(PMMA), as constituents of the inner core. See, e.g., Zhao et al., Langmuir (1990) 6, 514-516; Zhang et al., Science (1995) 268, 1728-1731; Inoue et al., J. Controlled Release (1998) 51, 221-229 and Kataoka J. Macromol. Sci. Pure Appl. Chem. (1994) A31, 1759-1769. The hydrophobic inner core can also consist of a highly hydrophobic small chain such as an alkyl chain or a diacyllipid (e.g. distearoyl phosphatidyl ethanolamine). The hydrophobic chain can be either attached to one end of a polymer, or randomly distributed within the polymeric structure. The shell usually consists of chains of hydrophilic, non-biodegradable, biocompatible polymers such as poly(ethylene oxide) (PEO) (see Allen et al. Colloids Surf. B: Biointerf. (1999) 16, 3-27 and Kataoka et al. J. Controlled Release (2000) 64, 143-153), poly(N-vinyl-2-pyrrolidone) (PVP) (see Benahmed A et al. Pharm Res (2001) 18, 323-328) or poly(2-ethyl-2-oxazoline) (see Lee et al. Macromolecules (1999) 32, 1847-1852).
The biodistribution of the carrier is mainly dictated by the nature of the hydrophilic shell. Other polymers such as poly(N-isopropylacrylamide) and poly(alkylacrylic acid) impart temperature or pH sensitivity to the micelles, and could eventually be used to confer bioadhesive properties (see U.S. Pat. No. 5,770,627). Micelles presenting functional groups at their surface for conjugation with a targeting moiety have also been described (See, e.g., Scholz, C. et al., Macromolecules (1995) 28, 7295-7297).
At the present time, most polymeric micelles described in the literature are prepared using non-ionizable block polymers or block copolymers where ionizable monomers are used to form the micelle corona whereas the core consists of a hydrophobic neutral homopolymer or copolymer. Ionizable diblock copolymers have been shown to exhibit pH-dependent micellization. Recently, Webber and Martin (U.S. Pat. No. 5,955,509) have described a type of pH-dependent micelles with a polyelectrolyte core. These micelles are composed of the diblock copolymers poly(vinyl N-heterocycle)-block-poly(alkylene oxide). Such copolymers are positively charged at acidic pH due to the protonation of the nitrogen atoms, and thus exist as unimers in acidic solutions. At high pH, the unprotonated copolymers self-associate into polymeric micelles. These micelles are primarily intended to deliver their contents at low pH, since the dissociation of the supramolecular assembly under acidic conditions allows a drug to be released. Such conditions may be found, for example in tumors. If intended to be administered by the oral route, these micelles would rapidly release their contents in the stomach because of its acidic pH. Therefore, for oral delivery, they should be formulated using an enteric coating to prevent premature drug leakage.
A potential problem with ionizable copolymers is the possibility of forming, at acidic pH, intra and inter-molecular hydrogen bonding between the protonated and the non-ionizable hydrophilic blocks which might lead to the formation of an insoluble complex. This has been recently described by Lele et al. J. Controlled Release (2000) 69, 237-248, between poly(acrylic acid) and poly(ethylene glycol). Precipitation of the micelles at acidic pH could potentially compromise the efficacy of the system when oral delivery is envisaged.
PICM have a block or graft copolymer architecture and consist of a polyelectrolyte linked to a non-ionic water-soluble polymer. They bind with charged compounds due to electrostatic interactions with the polyelectrolyte (see, e.g., Kataoka et al. Macromolecules (1996) 29, 8556-8557). The complexes self-assemble into micelle-like structures which have a hydrophobic core from neutralized polyelectrolyte and counterion, and hydrophilic corona. PICM show improved solubility compared with other electrostatic complexes. Furthermore, they show reduced affinity for plasma components and can protect active compounds such as DNA against enzymatic degradation.
Although, PICM hold great promise as carriers for a variety of selected from the group consisting of ionizable and permanently-charged diblock copolymers, ionizable and permanently-charged multiblock copolymers, and ionizable and permanently-charged random copolymers with grafted hydrophilic and essentially non-ionic oligomers or polymers compounds, such as charged drugs and nucleic acids, some important issues still remain to be addressed. For instance, the stability of the polymeric micelles is influenced by various factors such as concentration, temperature and chemical structure of the polymer. In particular, the presence of salts is a key parameter for the dissociation of PICM since Coulombic interactions between charged segments are screened by the added salt. To overcome this problem, polymeric micelles can be stabilized by cross-linking the core or shell (see, e.g., Kakizawa et al. J. Am. Chem. Soc. (1999) 121, 11247-11248). However, cross-linking the core or shell can potentially chemically alter the active agent and/or excessively slow down its release from the micelles.